Sarcoplasmic reticulum Ca decreases with age and correlates with the decline in muscle function in .

Sarcopenia, the loss of muscle mass and strength associated with age, has been linked to impairment of the cytosolic Ca peak that triggers muscle contraction, but mechanistic details remain unknown. Here we explore the hypothesis that a reduction in sarcoplasmic reticulum (SR) Ca concentration ([Ca]) is at the origin of this loss of Ca homeostasis. We engineered to express the Ca indicator GAP3 targeted to muscle SR, and we developed a new method to calibrate the signal into [Ca] [Ca] fell with age from ∼600 µM to 50 µM in close correlation with muscle function, which declined monotonically when [Ca] was <400 µM. [Ca] results from the pump-leak steady state at the SR membrane. However, changes in expression of the sarco/endoplasmic reticulum Ca-ATPase (SERCA) pump and of the ryanodine receptor leak were too modest to explain the large changes seen in [Ca] Instead, these changes are compatible with increased leakiness through the ryanodine receptor as the main determinant of the [Ca] decline in aging muscle. In contrast, there were no changes in endoplasmic reticulum [Ca] with age in brain neurons.This article has an associated First Person interview with the first author of the paper.